Kaneko et al U.S. Pat. No. 4,785,085 discloses rebeccamycin analogs which include 8-N-(diethylaminoethyl)rebeccamycin which has the formula: ##STR1## wherein n is 2 and R.sup.1 and R.sup.2 are each ethyl. The compound is referred to in Kaneko et al U.S. Pat. No. 4,785,085 as 6-(2-diethylaminoethyl)rebeccmycin and its preparation is described in Example 1 of the patent and its effectiveness to inhibit growth of tumors in experimental animal systems is shown in Table 3 of the patent. However, the compound is not sufficiently soluble in water when added thereto so as to form an aqueous injectable solution. Instead, it forms a suspension.
The technique of forming acid addition and base salts whereby the solubility of rebeccamycin analogs would be increased is suggested at column 9, lines 9 to 41 of Kaneko et al. The preparation of the hydrochloride salt of 8-N-(diethylaminoethyl)rebeccamycin is described in Example 2 of Kaneko et al where it is referred to as 6-(2-diethylaminoethyl)rebeccamycin hydrochloride and its effectiveness to inhibit growth of tumors in experimental animal systems is shown in Table 3 of the patent.
In respect to acid addition salts of 8-N-(diethylaminoethyl)rebeccamycin including the hydrochloride salt thereof, a problem encountered is that the crystalline acid addition salts, which contain one molar equivalent of acid reacted with the free base, when added to water in concentrations sufficient for use as, or dilution to, pharmaceutical dosage forms, do not form aqueous solutions which are sufficiently shelf stable. Rather, long term studies have revealed unusual physical instabilities over a period less than that which is considered acceptable for pharmaceutical compositions, namely at least 2 years at room temperature. These unexpected physical instabilities include gelling, precipitation, cloudiness, and formation of liquid crystalline phases which render solutions of the crystalline salts unsuitable for practical use as, or for dilution with water to provide, injectable solutions.
The object herein is to provide an aqueous solution of 8-N-(diethylaminoethyl)rebeccamycin for injection or for dilution for injection which is substantially chemically and physically stable over a period of at least two years at room temperature.
The term "stable" is used hereinafter to mean substantially chemically and physically stable over a period of at least two years at room temperature when protected from light (e.g. by screening out light with an opaque material or by housing the solution in amber glass containers), when it is not otherwise qualified. The term "substantially chemically stable" means that analysis indicates the presence of at least 95% by weight of 8-N-(diethylaminoethyl)rebeccamycin initially dissolved is still in solution. The term "substantially physically stable" means the substantial absence of formation of a gel, precipitate, cloudiness or liquid crystalline phase, or other particulate matter which would make the solution unsuitable for injection.